Drug-eluting medical device

ABSTRACT

The present invention relates to a drug-eluting medical device, in particular a balloon for angioplasty catheters with drug elution to prevent the restenosis of the vessel subjected to angioplasty. More particularly, the present invention relates to a catheter balloon completely or partially coated with paclitaxel in hydrated crystalline form or in hydrated solvated crystalline form, having an immediate release and bioavailability of a therapeutically effective amount of paclitaxel at the site of intervention. The balloon can be made of a polyether-polyamide block copolymer, or a polyester amide, or polyamide-12.

The present invention relates to a drug-eluting medical device, inparticular a balloon for angioplasty catheters with drug elution toprevent restenosis of the vessel subjected to angioplasty.

BACKGROUND OF THE INVENTION

The treatment of vascular atherosclerotic lesions is a widespreadtherapy. Such lesions are most often localized at predetermined portionsof the blood vessels, of which they cause constrictions or alsoobstructions. Vascular atherosclerotic lesions are typically treated inangioplasty procedures by means of catheters provided with a balloon.

A catheter provided at the distal end thereof with a balloon isadvanced, following a guidewire, to the ostium of the narrowed artery.Once the balloon has been arranged at the artery narrowing, it isrepeatedly inflated and deflated. The insufflation, with successivedeflation, of the balloon within the artery reduce the extent of thearterial luminal narrowing, and restore a suitable blood flow in thecardiac area, suffering from the stenosis. In some cases, it isnecessary to arrange a so-called stent, which provides to maintain theartery patent also after withdrawal of the catheter and the balloon.

In both cases, success of the intervention is not complete. In fact,after a few months, some patients develop a new narrowing of the vesselwall at the intervention point. Such narrowing, known under the name ofrestenosis, is not due to the formation of new atherosclerotic plaques,but to a cell hyperproliferation process, particularly of the vascularsmooth muscle cells, probably due to the dilating action operated by theforeign body, stent or balloon.

It has been observed that restenosis can be treated by coating a stentwith a drug having antiproliferative action. Among the drugs usuallyemployed to such aim, paclitaxel (taxol) has proved to be particularlyefficient. The drug must be released for a sufficiently long time span,so as to inhibit the cell hyperproliferation process caused by theconstant presence of the stent implanted in the vessel. However, thedrug also induces an inhibition of the stent endothelization process,which is crucial to avoid the formation of thrombi. For this reasons,the use of a stent with drug elution (“drug eluting stent”) has somedrawbacks.

More recently, antiproliferative drug-coated catheter balloons have beenproposed. However, in almost all cases, forms of slow release of thedrug at the site of intervention after the drug has been transferredfrom the balloon to the vessel wall have been described.

However, it has been noticed that a drug elution over a prolonged timeframe to inhibit the restenosis phenomenon is neither necessary nordesirable, but that it is sufficient, and rather more convenient, a timelimited contact between drug and vessel surface, for example, from a fewseconds to one minute. These are typically the contact times of acatheter balloon as described before.

The patent publication WO 02/076509 discloses drug-coated catheterballoons releasing such drug in an immediately bioavailable form duringthe short contact time of the balloon with the vessel wall.

It will be recognized that an approach such as the one described hereinabove poses completely different problems compared to those previouslydealt with. In fact, while a prolonged drug elution can be obtained byvarious solutions, such as, for example, incorporation of the drug in apolymeric matrix or microcapsules, the immediate release will depend onseveral factors, of which the main ones are:

-   -   The nature of the drug, in particular the hydrophilicity or        hydrophobicity thereof;    -   The form in which the drug is administered, in particular, the        crystalline or amorphous form thereof;    -   The presence of possible excipients or “enhancers”;    -   Optionally, the nature of the balloon surface on which the drug        is deposited.

In fact, it should be understood that the drug has to be, first of all,released from the balloon to the vessel wall in the very short contacttime available during an angioplasty procedure. Once the drug has beenreleased, it has to be absorbed by the cell wall, before the blood flowwashes it off. Ideally, it is therefore desirable that the drugabsorption occurs concomitantly to the release thereof from the balloon.

However, it is just as well necessary that the drug is retained by theballoon surface in a manner sufficient to resist to all the handlingoperations which it is subjected to, both during the production step andduring the preparation and carrying out of the angioplasty procedure, inany case, before the balloon reaches the site of intervention. Thisrequires a perfect balance of such properties.

Therefore, it is an object of the present invention to provide acatheter balloon coated with a drug which allows an immediate releaseand bioavailability of the drug at the site of intervention.

It is a further object of the present invention to provide a method ofcoating of a catheter balloon with a drug in order to reach a goodadherence of the drug on the balloon surface and at the same time a fastrelease of the drug upon contact of the said balloon surface with ablood vessel wall.

SUMMARY OF THE INVENTION

The present invention relates to a catheter balloon coated withpaclitaxel in crystalline hydrated form, having an immediate release andbioavailability of the drug at the site of intervention.

A further object of the invention is a catheter balloon coated withpaclitaxel in crystalline hydrated solvated form, having an immediaterelease and bioavailability of the drug at the site of intervention.

According to another aspect of the invention, the catheter ballooncoated with paclitaxel in crystalline hydrated or solvated hydrated formas defined before is made of a polyether-polyamide block copolymer, or“compound” thereof with a polyamide.

According to a further aspect, the catheter balloon coated withpaclitaxel in crystalline hydrated or solvated hydrated form as definedbefore is made of a polyester amide.

According to a further aspect, the catheter balloon coated withpaclitaxel in crystalline hydrated or crystalline solvated hydrated formas defined before is made of polyamide-12.

According to a further aspect, the catheter balloon surface ishydrophilic or made hydrophilic by treatment with a hydrophilizingagent.

According to a further aspect of the invention, paclitaxel incrystalline hydrated or solvated hydrated form as defined before isdeposited from a urea-containing solution.

According to an aspect of the invention, the balloon is inflated beforecoating with the paclitaxel solution and then it is folded when stillwet. According to a further aspect of the invention, the balloon isfolded, then it is inflated before coating with the paclitaxel solutionand it is finally folded again when still wet.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic side view of a device for rotating a catheterballoon during coating, according to an aspect of the invention.

DESCRIPTION OF THE INVENTION

The present invention relates in particular to a catheter ballooncompletely or partially coated with paclitaxel in hydrated crystallineform, having an immediate release and bioavailability of atherapeutically effective amount of paclitaxel at the site ofintervention.

By the term “an immediate release and bioavailability” is meant arelease from the balloon surface in periods of time ranging between 1second and 1.5 minutes, preferably between 20 seconds and 1 minute, andan absorption by the vascular tissue in periods of time ranging between1 second and 25 minutes, preferably between 20 seconds and 25 minutes.

By the term “therapeutically effective amount” is meant a drug amountcapable of inducing a therapeutical or preventive effect against therestenosis of the treated vascular tissue in the patient.

By the term “site of intervention” is meant the section of the bloodvessel treated directly with the catheter balloon of the invention, andthe adjacent portion of the tissues in which the post-procedure presenceof paclitaxel can be detected. Generally, such section will extend for2-10 mm down- and upstream the contact section with the balloon.

With “paclitaxel in hydrated crystalline form” is meant paclitaxel with2, 3 or 4 molecules of water of crystallization.

This crystalline form of paclitaxel can be obtained by dissolvingpaclitaxel in an aqueous solvent, by completely or partially wetting theballoon surface with such solution, and by letting the solvent toevaporate to a formation of a crystalline layer having a white,homogeneous, or partially inhomogeneous appearance.

As the aqueous solvent, a mixture of solvents selected fromacetone/ethanol/water, tetrahydrofuran/water, methanol/water,acetone/water, ethanol/water, acetonitrile/water, DMF/water ispreferably used. More preferably, the solvent is a 9:1tetrahydrofuran/water mixture or a tetrahydrofuran/water mixture withratios ranging between 9.5:0.5 and 65:35, or an acetone/ethanol/watermixture in which the organic solvent is present in amounts not less than50% by volume relative to water.

The concentration of paclitaxel in the solution may range from 4 to 6mg/ml, preferably about 5 mg/ml.

The balloon wetting step can be performed in several ways, known tothose skilled in the art, such as, for example, dipping the balloon intothe paclitaxel solution, spraying the paclitaxel solution on theballoon, or depositing the paclitaxel solution on the balloon by meansof a syringe, a micropipette, or other similar dispensing device.

The balloon can be wetted with the paclitaxel solution in a deployed andinflated condition, or in a folded condition. It has been observed thatin this second case also, the paclitaxel solution penetrates bycapillarity under the folds, so as to form a drug depot which remainsprotected during the introduction step of the folded balloon into theblood vessel by means of the catheter, until reaching the site ofintervention and the inflation thereof.

Methods are also known to selectively coat the area under the balloonfolds, leaving the outer surface substantially free from the drug. Suchmethods can comprise, for example, the introduction into the balloonfolds of a cannula bearing a series of micro-nozzles, through which thepaclitaxel solution is deposited on the inner surface of the folds. Sucha method is described, for example, in the international application No.PCT/IT2007/000816, filed on Nov. 21 2007, the contents of which areincorporated herein by reference.

The folded balloon will preferably have 3 to 6 folds.

A preferred wetting method for the balloon is the deposition of thepaclitaxel solution on the folded balloon surface by means of a syringe,micropipette, or other similar dispensing means. Typically, thedispensing means will be made to slide on the surface from an end to theother one, and vice versa, while rotating the balloon around thelongitudinal axis thereof, so as to establish a zigzag path.Alternatively, the dispensing means will be made to slide on the balloonsurface starting from a substantially central position relative to thelongitudinal extent thereof, and it will be made to slide towards afirst end thereof and, subsequently, towards the second end thereof, soas to establish a substantially zigzag path.

According to a further method, the following steps are performed:

-   -   (a) Providing a balloon;    -   (b) Inflating the said balloon to a predetermined pressure;    -   (c) Coating the said inflated balloon of step    -   (b) with a paclitaxel solution;    -   (d) Deflating the coated balloon of step (c);    -   (e) Folding the deflated balloon of step (d) when still wet;    -   (f) Optionally, applying to the said folded balloon a protective        cover.

According to this method the coating step is performed directly duringthe manufacturing process of the balloon catheter and the coating stepis indeed part of the balloon catheter manufacturing process. Therefore,the production of a coated balloon catheter according to this method isadvantageously quicker.

According to a further preferred method, the following steps areperformed:

-   -   (g) Providing a folded balloon, for example a balloon having 3        or 6 folds;    -   (h) Inflating the said folded balloon to a predetermined        pressure;    -   (i) Coating the said inflated balloon of step    -   (h) with a paclitaxel solution;    -   (j) Deflating the coated balloon of step (i);    -   (k) Re-folding the deflated balloon of step (j) when still wet;    -   (l) Optionally, applying to the said re-folded balloon a        protective cover.

The use of an already folded balloon according to step (g) isadvantageous because the material may keep some memory of the folds evenafter inflation in step (h), so that the subsequent re-folding of step(k) can take place easily and in a short time, without manipulating toomuch the coated balloon.

The said predetermined pressure in step (b) or (h) is a pressure belowthe nominal pressure (RBP pressure) of the balloon. For example, forballoon diameters between 4 and 7 mm and balloon length between 40 and80 mm, the said predetermined pressure is between 5 and 9 bar.

The inflated balloon of step (b) or (h) is preferably disconnected fromthe pressurised air source before coating. In such a way, the balloon isstill inflated, but it is not tensioned and the coating stepadvantageously benefits from this state condition. In the case of longballoons, inflation step (b) or (h) is prolonged for less than 1 minute.

Coating of step (c) or (i) is preferably performed by delivering thedrug solution over the inflated balloon surface. Typically, amicropipette can be used, as described above for the coating of thefolded balloons. The same protocol can be followed, i.e. startingdelivery of the solution from the mid of the balloon length and movingto an end of the balloon, then to the opposite end, while the balloon isrotated. It is important that substantially the whole balloon surface iswetted.

Preferably, the rotation of the balloon is not too fast. Typically, arotational speed of the balloon during coating from about 5 rpm to about30, preferably from about 10 rpm to about 20 rpm, is used, but differentvalues may be set without departing from the scope of the invention.Preferably, the delivery time of the drug solution may range from about10 seconds to about 500 seconds.

The rotation of the balloon may preferably be accomplished by means of adevice as shown in FIG. 1 and as described below.

Step (d) or (j) of deflation of the coated balloon is accomplished byapplying vacuum to the catheter balloon opening and/or by pressing theballoon from the exterior. Application of vacuum is preferred, inparticular for long balloons.

Step (e) or (k) of folding and re-folding respectively is performed bymeans of conventional devices for folding balloons.

According to the processes mentioned above, folding (e) and re-folding(k) are performed when the balloon surface is still wet. This allows abetter adherence of drug onto the balloon surface to be obtained.

Typically, the said folding (e) or re-folding (k) is performed within 20minutes from the end of the coating step (c) or (i) respectively,preferably between 1 minute and 10 minutes, more preferably between 1minute and 5 minutes.

If performed, step (f) or step (1) are accomplished by inserting overthe folded or re-folded balloon a protective cover, typically a sleevethat envelops the balloon surface that has been coated with the drug.Such a sleeve is preferably made of a low friction material.

As a low friction material, polytetrafluoroethylene (PTFE) mayconveniently be used. The use of a low friction material allows tominimize the removal of the drug adhered onto the balloon surface. Thelow friction material should have a friction coefficient below thefriction coefficient of the material of which the balloon is made.

In general, independently from the method used, it is possible to repeatseveral times the balloon wetting step with the paclitaxel solution, asa function of the drug amount which is intended to be deposited.

As shown in FIG. 1, a suitable device for rotating a catheter balloon 2is indicated with the numeral 1. The catheter balloon 2 comprises acatheter section 3 and a balloon section 4, that is shown in theinflated condition.

The device 1 comprises a basement 4, a first motor unit 5 and a secondmotor unit 6. Each motor unit 5, 6 comprises clamping means 8, 8′ toclamp the two ends of the catheter balloon 2.

Preferably, the distal clamping means 8 acts upon the guide wire (notshown) on which the catheter balloon is loaded. Preferably, the proximalclamping means 8′ acts upon the connector (luer) (not shown) thecatheter balloon is provided with.

The motor units 5, 6 are preferably brushless motors. The motor units 5,6 are synchronously operated. A command and control unit 7 provides forthe synchronous operation of the two motor units 5, 6. This isimportant, in order to avoid torsion of the catheter balloon 2.

One or more supporting means 9, depending on the balloon length, arealso provided in order to keep the catheter balloon 2 in an horizontalposition.

According to another aspect, the invention relates to a catheter ballooncompletely or partially coated with paclitaxel in crystalline hydratedsolvated form, having an immediate release and bioavailability of atherapeutically effective amount of paclitaxel at the site ofintervention.

With “paclitaxel in crystalline hydrated solvated form” is meantpaclitaxel with 2 to 3 molecules of water of crystallization and with 1to 3 molecules of solvent.

It shall be noted that, both in the case of the hydrated crystallineform and the hydrated solvated crystalline form as defined before,paclitaxel tends to form dimers which take in water and/or the solventinto the crystalline structure. Therefore, it is possible that thenumber of molecules of water of crystallization or solvent into thesolvate per molecule of paclitaxel is not defined by an integer, but bya decimal. For example, if a hydrated solvate is formed bycrystallization from a solvent such as dioxane/water, a dimer can beobtained, which takes in 5 water molecules and 3 dioxane molecules: inthis case, therefore, there will be 2.5 molecules of water ofcrystallization and 1.5 molecules dioxane per molecule of paclitaxel.

The crystalline hydrated solvated form of paclitaxel can be obtainedfrom an aqueous solvent preferably selected from dioxane/water,DMF/water, DMSO/water, N-methylpyrrolidone/water, acetonitrile/water,N,N-dimethylacetamide/water,1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone/water,1,3-dimethyl-2-imidazolidinone/water mixtures, or mixtures thereof, byoperating under suitable conditions, such as those described in thepatent publication WO 03/0475078 in the name of Bristol-Myers SquibbCo., the content of which, relatively to such preparation methods, isincorporated herein by reference.

The preparation modes of the balloon completely or partially coated withpaclitaxel in crystalline hydrated solvated form are completely similarto those described above for the hydrated crystalline form; therefore,they will not be further described.

According to a further aspect of the invention, a catheter ballooncompletely or partially coated with paclitaxel in crystalline hydratedor crystalline solvated hydrated form, having an immediate release andbioavailability of a therapeutically effective amount of paclitaxel atthe site of intervention, can be obtained by dissolving paclitaxel in anaqueous solvent, as defined before, in the presence of urea, bycompletely or partially wetting the balloon surface with such solution,and by letting the solvent to evaporate to the formation of acrystalline layer having a white, homogeneous, or partiallyinhomogeneous appearance.

It has been noticed that the presence of urea in the coating layer ofpaclitaxel on the balloon surface promotes the release of the drug fromsuch surface. Urea can be used in amounts ranging between 1 and 100 mgper mL solvent, preferably between 4 and 10 mg per mL solvent, morepreferably about 7 mg per mL solvent.

It is a further object of the present invention a catheter ballooncompletely or partially coated with paclitaxel in crystalline hydratedor crystalline solvated hydrated form, having an immediate release andbioavailability of a therapeutically effective amount of paclitaxel atthe site of intervention, in which said balloon is made of apolyether-polyamide block copolymer or “compound” thereof with apolyamide.

The polyether-polyamide block copolymer according to the invention is anelastomer comprising polyamide block-forming monomers, representing thehard portion of the material, modified with a group representing thesoft portion.

This elastomer is obtained by polymerization of a polyamideblock-forming compound selected from the group consisting of anaminocarboxylic acid according to the formula (1) and a lactam accordingto the formula (2):

with a triblock polyetherdiamine compound of formula (3):

-   -   and with a dicarboxylic acid according to the formula (4):

HOOC—(R3)_(m)-COOH  (4)

In the above-mentioned formulae, each of the R1, R2, and R3 groupsrepresents linking groups comprising a hydrocarbon chain therein,optionally interrupted by one or more amide groups.

Preferably, R1 and R2 independently comprise an alkylene group having 2to 20 carbon atoms and amide bonds, and R3 comprises an alkylene grouphaving 1 to 20 carbon atoms;

x can vary between 1 and 20, preferably between 1 and 18, morepreferably between 1 and 16; y can vary between 4 and 50, preferablybetween 5 and 45, more preferably between 8 and 30, and z can varybetween 1 and 20, preferably between 1 and 18, more preferably between 1and 12;

m is 0 or 1.

Generally, the polymerization is carried out by using 15 to 70% byweight of the compound of formula (1) and/or (2), and a mixture ofcompounds of formulae (3) and (4) in an overall weight percentagebetween 30 and 85%. This polymerization is carried out in a reactor at atemperature ranging between 150 and 300° C., preferably between 160 and280° C., more preferably between 180 and 250° C.

Compounds of such copolymers with polyamides can be obtained by mixing,according to known techniques, the copolymer in amounts from 10 to 90%by weight, preferably 75 to 25%, more preferably 60 to 40% by weight,with an amount of polyamide to completion of 100%.

Preferably, the polyamide is polyamide-12.

Such copolymers and the compounds thereof with polyamides are known, andhave been described in detail in the patent publication WO 2007/132485A1, the content of which, relatively to the structure of such materials,and obtaining thereof, is incorporated herein by reference.

It has been observed that the use of such material in the constructionof the catheter balloon of the invention provides optimalcharacteristics of paclitaxel release, while balancing the necessaryability of retaining the drug during the processing and use steps farfrom the site of intervention with the easiness to release thepaclitaxel layer to the vascular cell wall in the short contact timebetween this and the inflated balloon surface, at the site ofintervention.

It is a further object of the present invention a catheter ballooncompletely or partially coated with paclitaxel in crystalline hydratedor crystalline solvated hydrated form, having an immediate release andbioavailability of a therapeutically effective amount of paclitaxel atthe site of intervention, in which said balloon is made of polyamide-12.

It is a further object of the present invention a catheter ballooncompletely or partially coated with paclitaxel in crystalline hydratedor crystalline solvated hydrated form, having an immediate release andbioavailability of a therapeutically effective amount of paclitaxel atthe site of intervention, in which said balloon is made of polyesteramide.

The polyester amide used in the present invention can be described bythe following general formula:

H—(O—PF—OOC—PA-COO—PF—OOC—PA-OO)_(n)—OH

in which PA is a polyamide segment, PF is a diol segment comprisingOH-terminating dimer diol segments, and n is a number ranging between 5and 20.

The content of the diol component within the polyester-amide copolymeris 5-50% by weight. Preferably, the concentration of the diol componentranges between 10 to 30% by weight, still more preferably between 10 and20% by weight of the total formulation.

These polymers are known, and have been described in detail in thepatent publication WO 2005/037337 A1, the content of which, relativelyto the chemical structure and the preparation methods of such materials,is incorporated herein by reference.

It is a further object of the present invention a catheter ballooncompletely or partially coated with paclitaxel in crystalline hydratedor crystalline solvated hydrated form, having an immediate release andbioavailability of a therapeutically effective amount of paclitaxel atthe site of intervention, in which said balloon has a surface which ishydrophilic or hydrophilized by suitable hydrophilizing treatment.

For example, the catheter balloon surface according to the invention canbe made hydrophilic by treatment with plasma-activated oxygen.

In all the above-described embodiments, paclitaxel is present in thecatheter balloon coating layer in amounts ranging between 1 and 20μg/mm², preferably between 2 and 7 μg/mm², more preferably between 3 and5 μg/mm².

The invention will now be further described by means of the followingexamples, given by way of non-limiting example.

Example 1A—Coating of Catheter Balloons with Crystalline Hydrated orCrystalline Hydrated Solvated Paclitaxel

Paclitaxel solutions have been prepared at a 50 mg/mL concentration inthe following solvents:

(1) 9:1 THF/water

(2) 9:1 THF/water with addition of 15 mg/mL urea

(3) 6.5:3.5 THF/water

(4) Acetone/ethanol/water

(5) Acetic acid (comparative solution)

(6) Dichloromethane (comparative solution)

It shall be noted that paclitaxel in a crystalline hydrated or solvatedhydrated form according to the invention is not obtained bycrystallization from acetic acid. Instead, amorphous paclitaxel isobtained by precipitation from dichloromethane.

Some balloons—made of a polyamide-12+polyether-polyamide block copolymercompound (70% UBESTA® XPA9063+30% UBESTA® 3030XA) and in a foldedcondition—have been coated with paclitaxel by wetting the surfacethereof with equal volumes of the solutions (1)-(6) by means of aHamilton syringe, according to the previously described modes. For eachsolution, several balloons have been used.

Then, the balloons have been dried under vacuum.

The appearance of the coating was white, not always homogeneous.

Example 1B—Coating of Catheter Balloons with Crystalline Hydrated orCrystalline Hydrated Solvated Paclitaxel (Coating in an UnfoldedCondition)

The procedure of example 1A has been repeated using coating solution(2), by inflating first the folded balloons at 7 bar, then removing thepressurised air source and coating the inflated balloons by means of aHamilton syringe. The coated balloons have then been re-folded afterabout 1 minute after the coating step, while the surface thereof wasstill wet.

The appearance of the coating was white, substantially homogeneous.

Example 2—Assessment of Paclitaxel Adhesion on the Surface of theCatheter Balloons

The balloons prepared according to the example 1 have been subjected tosome assessments, in order to determine the drug adhesion under thevarious conditions.

Test A

First, the dry adhesion has been assessed, which is useful to determinethe paclitaxel loss which can occur in the production or handling stepsof the balloon. Such determination has been carried out by dry expandingthe balloon and shaking the inflated balloon within a tube.

The paclitaxel content in the tube was determined by HPLC/UV. The drugwas taken up with ethanol, the tubes were closed and vigorously vortexedfor at least 30 seconds, followed by a treatment in an ultrasound bathfor 30 minutes. At least 70 μl of extract were injected into the HPLC,together with a paclitaxel standard solution (concentration of about 20μg/mL). The results are reported in Table I.

Test B

Release of paclitaxel at the site of intervention has been assessed inexperiments on castrated male pigs, approximately 3 months old, andweighing about 30 kg. The pigs were sedated by intramuscular injectionof ketamine and xylazine. Anaesthesia was started by intravenousinjection of propofol, followed by orotracheal intubation, and wasmaintained with 1-2 vol % isoflurane, vol % N₂O₂, and 30 vol % oxygen.All the animals received 5.000 IU heparin, 250 mg aspirine, and 200 mgnitroglicerine via the intracoronary route. The coronary arteries weremonitored by means of a standard angiography technique through the leftcarotid artery.

The animals were treated with the paclitaxel-coated balloons (solutions(1)-(6)) mounted on catheter.

Some balloons, once the site of intervention has been reached, were keptfloating in the blood flow for 1 minute without expanding them, thenthey were retracted, introduced into suitable tubes, inflated, andseparated from the catheter. After that, they were extracted withethanol as described in test A, and finally subjecting the tube tocentrifugation for 10 minutes. The extracts were analyzed by HPLC/UV aspreviously described, so as to determine the paclitaxel amount which isdispersed in the blood flow. The results are reported in Table I.

Other balloons, on which stents had been mounted, have instead beenintroduced, inflated, and then deflated and retracted, then undergoingthe same extraction treatment of those non-inflated. In this case, theresidual paclitaxel amount left on the balloon after contacting thevessel wall was determined.

After a period of time ranging between 15 and 25 minutes, the animalswere sacrificed by administration of 20% KCl under deep anaesthesia.Hearts were quickly removed, and the arterial segments on which thestent was arranged, plus a portion 5 mm down- and upstream the stent,were sectioned, placed in pre-weighted tubes to determine the weightthereof, and subjected to extraction with a predetermined amount ofethanol to achieve a >50% concentration. After 30 minutes of extractionat room temperature with ultrasounds and centrifugation for 10 minutes,the extracts were analyzed by HPLC/UV as described before, so as todetermine the paclitaxel amount absorbed by the vascular tissue. Theresults are reported in Table I.

TABLE I Results of drug adhesion, release, and uptake by the vasculartissue % paclitaxel lost in blood % paclitaxel % paclitaxel % paclitaxelflow (non- not released absorbed by Deposition lost by dry inflated tothe site of the vascular solution expansion balloon) intervention tissue(1) 4 ± 3 22 ± 3  32 ± 9  13.3 ± 7.3  (2)/EX. 24 ± 1  42 ± 3  13 ± 3 19.7 ± 11.3 1A (2)/EX. 7 ± 4 27 ± 17 16 ± 8  17.7 ± 11.9 1B (3) 10 ± 5 26 ± 11 30 ± 6  17.4 ± 5.5  (4) 11 ± 11 33 ± 13 9 ± 4 23.4 ± 8.1  (5) 3± 2 5 ± 4 64 ± 5  5.2 ± 3.2 (6) 4 ± 3 41 ± 26 11 ± 7  17.4 ± 7.2 

Data reported in Table I show that paclitaxel release is noticeablyhigher when the drug is present in crystalline hydrated or solvatedhydrated form (lines (1) to (4)) compared to the non-hydrated form (line(5)). In fact, in the latter case, most paclitaxel (64%±5%) remainsadhered to the balloon surface, and the drug amount absorbed by thevascular tissue is only 5.2%±3.2%.

As regards paclitaxel in the amorphous form (line (6)), although datashow a high amount of drug released by the balloon and absorbed into thetissues, further experiments for the restenosis inhibition assessmentdemonstrated an inactivity of such form. In such further experiments,paclitaxel in crystalline hydrated or solvated hydrated form (lines(1)-(4)) exhibited, instead, a restenosis inhibition action in theanimal.

Data also show that the presence of urea in the deposition solution(line (2)) produces a higher paclitaxel release and a higher amount ofdrug absorbed in the vascular tissue, compared to the same solutionwithout the presence of urea (line (1)).

The coating in the inflated state, followed by re-folding while stillwet, allows a better adherence of the drug onto the balloon surface.

Further investigations demonstrated that the material of which theballoon is made has also a considerable impact on the paclitaxel releaseproperties, the polyether-polyamide block copolymer, or the compoundthereof with polyamides giving the best results for drug elution.

Example 3—Determination of the Crystalline Form of Paclitaxel

Paclitaxel in crystalline hydrated form was identified by IR analysisunder the conditions reported in the literature, thus obtaining aspectrum which was equivalent to what has been described in Jeong HoonLee et al., Bull. Korean Chem. Soc. 2001, vol. 22, No. 8, 925-928.

1-41. (canceled)
 42. A catheter balloon coated with paclitaxel incrystalline form, having an immediate release and bioavailability of atherapeutically effective amount of paclitaxel at a site ofintervention, wherein: the paclitaxel is present in a catheter ballooncoating layer that does not comprise a polymer, and the paclitaxelconsists essentially of (i) paclitaxel in crystalline hydrated form,(ii) paclitaxel in crystalline hydrated solvated form, or (iii)paclitaxel in crystalline hydrated form and paclitaxel in crystallinehydrated solvated form.
 43. The catheter balloon of claim 42, whereinthe coating layer consists essentially of (i) paclitaxel in crystallinehydrated form, (ii) paclitaxel in crystalline hydrated solvated form, or(iii) paclitaxel in crystalline hydrated form and paclitaxel incrystalline hydrated solvated form.
 44. The catheter balloon of claim42, wherein the paclitaxel comprises paclitaxel in crystalline hydratedform.
 45. The catheter balloon of claim 44, wherein the crystallinehydrated form comprises water of crystallization in a molar ratioexpressed by an integer or a decimal ranging between 2 and 4 permolecule of paclitaxel.
 46. The catheter balloon of claim 42, whereinthe paclitaxel comprises paclitaxel in crystalline hydrated solvatedform.
 47. The catheter balloon of claim 46, wherein the crystallinehydrated solvated form comprises water of crystallization in a molarratio expressed by an integer or a decimal from 2 to 3, and solvatingsolvent in a molar ratio expressed by an integer or a decimal from 1 to3 per molecule of paclitaxel.
 48. The catheter balloon of claim 42,wherein the paclitaxel is present in a catheter balloon coating layer inamounts ranging between 1 and 5 μg/mm².
 49. The catheter balloon ofclaim 42, wherein the release of a therapeutically effective amount ofthe paclitaxel occurs in a period of time ranging between 1 second and1.5 minutes.
 50. The catheter balloon of claim 42, wherein thebioavailability of the therapeutically effective amount of thepaclitaxel occurs in periods of time ranging between 1 second and 25minutes.
 51. The catheter balloon of claim 42, wherein the coating layeris deposited on the balloon in a zigzag path.
 52. The catheter balloonof claim 42, wherein the coating layer comprises urea.
 53. The catheterballoon of claim 42, wherein the balloon comprises a polyether-polyamideblock copolymer, or compound thereof with a polyamide.
 54. The catheterballoon of claim 42, wherein the balloon is made of polyamide-12. 55.The catheter balloon of claim 42, wherein the balloon is made ofpolyester amide.
 56. The catheter balloon according to claim 42, whereinthe balloon has a surface which is hydrophilic or hydrophilized bysuitable hydrophilizing treatment.
 57. A method comprising: dissolvingpaclitaxel in an aqueous solvent so as to form a paclitaxel solution,wherein the paclitaxel consists essentially of (i) paclitaxel incrystalline hydrated form, (ii) paclitaxel in crystalline hydratedsolvated form, or (iii) paclitaxel in crystalline hydrated form andpaclitaxel in crystalline hydrated solvated form, and wherein thepaclitaxel solution does not comprise a polymer; wetting a surface of aballoon catheter with the paclitaxel solution; and allowing the solventto evaporate to form a catheter balloon coated with paclitaxel incrystalline form, having an immediate release and bioavailability of atherapeutically effective amount of paclitaxel at a site ofintervention.
 58. The method of claim 57, wherein the aqueous solvent isselected from acetone/ethanol/water, tetrahydrofuran/water,methanol/water, acetone/water, ethanol/water, acetonitrile/water,DMF/water mixtures for crystalline hydrated paclitaxel, and fromdioxane/water, DMF/water, DMSO/water, N-methylpyrrolidone/water,acetonitrile/water, N,N-dimethylacetamide/water,1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone/water,1,3-dimethyl-2-imidazolidinone/water mixtures, or mixtures thereof, forcrystalline hydrated solvated paclitaxel.
 59. The catheter balloon ofclaim 58, wherein the aqueous solvent for the formation of paclitaxel incrystalline hydrated form is selected from a 9:1 tetrahydrofuran/watermixture, or a tetrahydrofuran/water mixture with ratios ranging between9.5:0.5 and 65:35, or an acetone/ethanol/water mixture, in which theorganic solvent is present in an amount not less than 50% by volumerelative to water.
 60. The method of claim 57, wherein the paclitaxelsolution further comprises urea.
 61. The method of claim 60, wherein thepaclitaxel solution comprises urea in an amount in a ranging between 1and 100 mg/mL.
 62. The method of claim 57, wherein the paclitaxelsolution comprises a concentration between 4 and 6 mg/ml of paclitaxel.